Role of a cluster of long noncoding RNA transcripts in protecting the heart from pathological hypertrophy

Patent metadata

Field	Value
Publication number	US-9844583-B2
Application number	US-201514884827-A
Country	US
Kind code	B2
Filing date	Oct 16, 2015
Priority date	Oct 24, 2014
Publication date	Dec 19, 2017
Grant date	Dec 19, 2017

Abstract

Nucleic acids encoding modified myosin heavy-chain-associated RNA transcripts are provided. The modified myosin heavy-chain-associated RNA transcripts belongs to a cluster of long noncoding RNAs (lncRNA) and bind to chromatin remodeler Brg1 to inhibit Brg1's genomic targeting and gene regulation function. The modified myosin heavy-chain-associated RNA transcripts expressed in an individual inhibit Brg1's gene regulation function and protect the heart of the individual from myopathy and failure. One of the modified heavy-chain-associated RNAs is a 400 base pair fragment segmented from a natural 779 base pair sequence of Mhrt (Mhrt779) and has the same cardioprotective effects as the Mhrt779.

First claim

What is claimed is:

1. A composition comprising a nucleic acid encoding a modified myosin heavy-chain-associated RNA transcript, wherein the modified myosin heavy-chain-associated RNA transcript inhibits Brg1's genomic targeting and gene regulation function in a subject to whom the composition is administered,
wherein the modified myosin heavy-chain-associated RNA transcript comprises SEQ ID NO: 2.

2. A composition comprising a nucleic acid encoding a modified myosin heavy-chain-associated RNA transcript, wherein the modified myosin heavy-chain-associated RNA transcript inhibits Brg1's genomic targeting and gene regulation function in a subject to whom the composition is administered,
wherein the modified myosin heavy-chain-associated RNA transcript comprises SEQ ID NO: 4.

3. The composition of claim 1 , wherein the nucleic acid is incorporated into a vector.

4. The composition of claim 3 , wherein the vector comprises an expression cassette comprising a promoter operably linked to the nucleic acid encoding the modified myosin heavy-chain-associated RNA transcript, and wherein the promoter directs an expression of the nucleic acid to produce the modified myosin heavy-chain-associated RNA transcript.

5. The composition of claim 4 , wherein the promoter comprises an inducible promoter.

6. The composition of claim 5 , wherein the promoter comprises a tetracycline response element.

7. A non-human organism carrying a transgene comprising a promoter and a nucleic acid encoding a modified myosin heavy-chain-associated RNA transcript,
wherein the promoter regulates an expression of the nucleic acid to produce the modified myosin heavy-chain-associated RNA transcript in the organism, and
wherein the modified myosin heavy-chain-associated RNA transcript inhibits Brg1's genomic targeting and gene regulation function in the organism; and
wherein the modified myosin heavy-chain-associated RNA transcript is selected from the group consisting of: SEQ ID NO: 2 and SEQ ID NO: 4.

8. The non-human organism of claim 7 , wherein the transgene is incorporated into a genome DNA of the organism.

9. The non-human organism of claim 7 , wherein the promoter comprises an inducible promoter.

10. The non-human organism of claim 9 , wherein the promoter comprises a tetracycline response element.

11. The non-human organism of claim 8 , wherein the organism is a transgenic mouse carrying the transgene.

12. The non-human organism of claim 11 , wherein the promoter comprises a tetracycline response element, and wherein the nucleic acid encoding the modified myosin heavy-chain-associated RNA transcript expresses the modified myosin heavy-chain-associated RNA transcript in cardiomyocytes of the transgenic mouse in the presence of tetracycline or a tetracycline analog.

13. A method comprising:
administering to a subject a composition comprising a nucleic acid encoding a modified myosin heavy-chain-associated RNA transcript to express the modified myosin heavy-chain-associated RNA transcript in the subject,
wherein the modified myosin heavy-chain-associated RNA transcript inhibits Brg1's genomic targeting and gene regulation function in the subject; and
wherein the modified myosin heavy-chain-associated RNA transcript is selected from the group consisting of: SEQ ID NO: 2 and SEQ ID NO: 4.

14. The method of claim 13 , wherein the composition comprises a vector, and wherein the nucleic acid encoding the modified myosin heavy-chain-associated RNA transcript is incorporated in the vector.

15. The method of claim 14 , wherein the vector comprises an expression cassette comprising a promoter operably linked to the nucleic acid encoding the modified myosin heavy-chain-associated RNA transcript, and wherein the promoter regulates an expression of the nucleic acid to produce the modified myosin heavy-chain-associated RNA transcript in the subject.

16. The method of claim 13 , wherein the nucleic acid is incorporated into a genome DNA of the subject.

17. The method of claim 15 , wherein the promoter comprises an inducible promoter.

18. The method of claim 17 , wherein the promoter comprises a tetracycline response element.

19. The method of claim 17 , wherein the nucleic acid expresses the modified myosin heavy-chain-associated RNA transcript in cardiomyocytes of the subject under an induction of doxycycline treatment.

20. The method of claim 15 , wherein the composition is administered to the subject with a pharmaceutical carrier.

21. The method of claim 15 , wherein the composition is administered to the subject via injection.

22. The method of claim 21 , wherein the composition is administered to the subject through intravenously injection.

23. The method of claim 21 , wherein the composition is administered to the subject through intracardiac injection.

24. A treatment delivery apparatus comprising a device and at least one dosage of a composition contained in the device,
wherein the composition comprises a nucleic acid encoding a modified myosin heavy-chain-associated RNA transcript,
wherein the modified myosin heavy-chain-associated RNA transcript inhibits Brg1's genomic targeting and gene regulation function in a subject to whom the composition is administered; and
wherein the modified myosin heavy-chain-associated RNA transcript is selected from the group consisting of: SEQ ID NO: 2 and SEQ ID NO: 4.

25. The treatment delivery apparatus of claim 24 , wherein the composition comprises a vector, and wherein the nucleic acid encoding the modified myosin heavy-chain-associated RNA transcript is incorporated in the vector.

26. The treatment delivery apparatus of claim 25 , wherein the vector comprises an expression cassette comprising a promoter operably linked to the nucleic acid encoding the modified myosin heavy-chain-associated RNA transcript, and wherein the promoter directs an expression of the nucleic acid to produce the modified myosin heavy-chain-associated RNA transcript.

27. A method comprising:
administering to a subject a composition comprising a modified myosin heavy-chain-associated RNA transcript;
wherein the modified myosin heavy-chain-associated RNA transcript inhibits Brg1's genomic targeting and gene regulation function in the subject; and
wherein the modified myosin heavy-chain-associated RNA transcript is selected from the group consisting of: SEQ ID NO: 2 and SEQ ID NO: 4.

28. The method of claim 27 , wherein the composition comprises nanoparticles, and wherein the modified myosin heavy-chain-associated RNA transcript is packaged with the nanoparticles.

29. The composition of claim 2 , wherein the nucleic acid is incorporated into a vector.

30. The composition of claim 29 , wherein the vector comprises an expression cassette comprising a promoter operably linked to the nucleic acid encoding the modified myosin heavy-chain-associated RNA transcript, and wherein the promoter directs an expression of the nucleic acid to produce the modified myosin heavy-chain-associated RNA transcript.

31. The composition of claim 30 , wherein the promoter comprises an inducible promoter.

32. The composition of claim 31 , wherein the promoter comprises a tetracycline response element.

Assignees

• Univ Indiana Res & Tech Corp
• Indiana Univ Research And Technology Corp

Inventors

• Chang Ching-Pin

Classifications

• A01K2267/0375

  Animal model for cardiovascular diseases · CPC title

• C12Y306/04

  acting on acid anhydrides; involved in cellular and subcellular movement (3.6.4) · CPC title

• C12N2310/20

  involving clustered regularly interspaced short palindromic repeats [CRISPR] · CPC title

• A01K2217/203

  Animal model comprising inducible/conditional expression system, e.g. hormones, tet · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title